4-thiazoline-delta**2,alpha-acetic acid esters



United States Patent U.S. Cl. 260-306.7 7 Claims ABSTRACT OF THE DISCLOSURE This invention relates to certain thiazolineacetic acid esters, particularly 4 thiazoline A acetic acid esters, to processes used for their preparation and to intermediates used in those processes. 1

More specifically, this invention relates to A -acetic acid esters of Formula I 4-thiazolinein which R represents a lower alkyl group containing from 1 to 2 carbon atoms such as the methyl or ethyl group and R represents a lower alkyl group containing from 1 to 3 carbon atoms, such as the methyl, ethyl or propyl groups.

The thiazolineacetic acid esters of this invention possess interesting pharmacological properties. More particularly, these thiazolineacetic acid esters exhibit utility as anti-inflammatory agents in standard pharmacological tests, for example, the tests similar to these described by Robert A. Turner in Screening Methods in Pharmacology Academic Press, page 152, based on the reduction of pedal inflammation.

The discovery of anti-inflammatory activity for the thiazolineacetic acid esters of this invention is noteworthy, especially when considered in the light of prior art. The thiazoline moiety, which is the most prominent feature of the compounds of this invention, is not a feature of the groups of compounds known to possess anti-inflammatory activity, see, for example, C. A. Winter in Drug Research Birkhauser Verlag, volume 10, page 139.

When the thiazolineacetic acid ethyl esters of this invention are employed as anti-inflammatory agents in warmblooded animals, e.g., rats, they may be administered orally, alone or in tablets comb ned with pharmacologically acceptable excipients, such as starch, milk, sugar and so forth. They may also be administered orally in the form of solutions in suitable vehicles such as vegetable oils.

The dosage of the thiazolineacetic acid esters of this invention will vary with the particular compound chosen and form of administration. Furthermore, it will vary with the particular host under treatment. Generally, the compounds of this invention are administered at a concentration level that affords protective effects without any deleterious side effects. These effective concentration levels are usually obtained with a therapeutic range of 10 mg. to 100 mg. per kilo per day, with a preferred range of mg. to mg. per kilo per day.

The thiazolineacetic acid esters of this invention arev readily prepared by the following general method.

A commercially available isothiocyanate of the formula R NCS (II) in which R is as defined above is condensed in the presence of an alkali metal lower alkoxide, for example, sodium ethoxide, in a lower alkanol, for example, ethanol, with the commercially available methyl or ethyl cyanoacetate (III, R =CH or C H respectively) yielding the sodium salt of a 3-alkylamino-2-cyano-3- mercaptoacrylic acid ester of Formula IV. For purposes of characterization, the 3-alkylamino-2-cyano-3-mercaptoacrylic acid ester may be obtained from its sodium salt by neutralization with an equivalent of hydrochloric acid, followed by recrystallization from ethanol.

The above solution of the sodium salt of the 3-alkylamino-2-cyano-3-mercaptoacrylic acid ester is treated with chloroor bromo-2-propanone to yield the corresponding 3 alkyl 2 cyano-4-hydroxy-4-methyl-A -thiazolidineacetic acid ester of Formula V. This intermediate may be conveniently obtained as a solid precipitate if this reaction is allowed to proceed at room temperature for 2 to 24 hours. Subsequent treatment of this intermediate with a dilute mineral acid, such as hydrochloric acid in an inert solvent, preferably chloroform, or by prolonged heating, for example, 24 hours, of the solution in which the intermediate V is formed, effects the dehydration of the intermediate of Formula V, yielding the thiazolineacetic acid esters of this invention of Formula I in which R and R are as defined above. However, in practicing this invention I have found it convenient to prepare the thiazolineacetic acid esters of Formula I by boiling the solution containing the above sodium salt and chloroor bromo-2-propanone for two hours, replacing the lower alkanol with an equal volume of chloroform and shaking the chloroform solution with a dilute solution of hydrochloric acid for five minutes. Subsequent evaporation of the chloroform solution affords the thiazolineacetic acid esters of Formula 1.

Alternatively, the thiazolineacetic acid esters of this invention may be prepared by the following method.

The sodium salt of the 3-alkylamino-2-cyano-3-mercaptoacrylic acid ester of Formula TV in whch R and R are as defined above, prepared as described above, is condensed with a propargyl halide, such as, for example, propargyl bromide of propargyl chloride, to yield the 3-alkyla-cyano-4-methylene-A '-thiazolidineacetic acid ester of Formula VI. I prefer to do this reaction in an inert solvent, preferably methanol or ethanol, at temperatures ranging from -80 C. and for a period of time ranging from two to 24 hours, preferably eight hours. Subsequent mild acid treatment of the intermediate of Formula VI, or of the reaction mixture from which it may be obtained, with an excess of dilute mineral acid, such as dilute hydrochloric acid, or a weak acid, such as acetic acid, converts the intermediate of Formula VI to the thiazolineacetic acid esters of Formula I of this invention in which R and R are as defined above.

The following formulae, in which R and R are as defined above, and X represents chlorine or bromine, and

examples will illustrate the scope of this invention. However, these examples are not to be construed as limiting this invention in scope or spirit.

R NII COOR' CzHsONa CIC NaS II. III. ON

CIIsC O CHzXl H /C=C\ S CN EXAMPLE I To a cold solution of sodium ethoxide (0.1 mole of sodium in 50 ml. of ethanol), 0.1 mole of ethyl cyanoacetate is added. The solution is cooled and 0.1 mole of methyl isothiocyanate is added. The mixture is cooled for three minutes and left at room temperature for one hour, to allow the completion of the formation of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester. This solution may be used as such for the preparation of the thiazolineacetic acid esters of Formula I, see below.

For purposes of characterization of the product of this reaction, the solution of the sodium salt is poured into 250 ml. of water and acidified in the cold with 50% hydro- COOR COOR 'chloric acid. The precipitate is filtered off and crystallized EXAMPLE 2 To a solution of the sodium salt of 3-(methylamino)- 2-cyano-3-mercaptoacrylic acid ethyl ester (prepared as described in Example 1 using 0.05 mole sodium, 0.05 mole methyl isothiocyanate and 0.05 mole ethyl cyanoacetate) in 40 ml. of ethanol, is added chlor-2-propan0ne (0.06 mole). The reaction mixture is allowed to stand at room temperature for 24 hours. The resulting precipitate is collected, washed with water and dried. The precipitate, u cyano 4-hydroxy-3,4-dimethyl-A -thiazolidineacetic acid ethyl ester (V, R =C H and R =CH (broad and strong), 2195, 1680 cmr is dissolved in 40 ml. of chloroform and shaken thoroughly with dilute hydr-ochloric acid for five minutes. The chloroform layer is separated, dried over sodium sulfate, filtered and evaporated. The residue is crystallized fromisopropanol and then ethylacetate to give e-cyano-3,4-dirnethy1-4-thiazo? 4 line-A "-acetic acid ethyl ester, (I, R =C H and R =CH M.P. 176 C.

.ggf 2195 and 1650 cm.'

In the same manner, but using an equivalent amount of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid methyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester, cyano-3,4-dirnethyl-4-thiazoline-A '"-acetic acid methyl ester is obtained.

In the same manner, but using an equivalent amount of the sodium salt of 3-(ethylamino).-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester, acyano-3-ethyl-4-rnethyl-4-thiazoline-A --acetic acid methyl and ethyl esters are obtained, respectively.

In the same manner, but using an equivalent amount of the sodium salt of 3-(propylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of S-(methylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, a cyano-3-propyl-4-methyl-4-thiazoline-A -acetic acid methyl and ethyl esters are obtained, respectively.

EXAMPLE 3 To a solution of the sodium salt of 3-(methylamino)- 2-cyano-3-mercaptoacrylic acid ethyl ester (prepared as described in Example 1 using 0.05 mole sodium, 0.05 mole methyl isothiocyanate and 0.05 mole ethyl cyanoacetate) in 40 ml. of ethanol, is added chloro-2-propanone (0.06 mole). The reaction mixture is boiled for two hours. The ethanol is evaporated and the residue dissolved in chloroform and shaken thoroughly with dilute hydrochloric acid for five minutes. The chloroform layer is separated, dried over sodium sulfate, filtered and evaporated. The residue is crystallized from isopropanol and then ethyl acetate to give a-cyano-3,4-climethyl 4 thiazoline-A -acetic acid ethyl ester M.P. 176 0., identical with the product obtained as described in Example 2.

In the same manner, but using an equivalent amount of the sodium salt of 3-(methylamino)-2-cyano-3-mercapto-acrylic acid methyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester, acyano-3-4-dimethyl-4thiazoline-A?-acetic acid methyl ester is obtained.

In the same manner, but using an equivalent amount of the sodium salt of 3-(ethylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of B-(methylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester, 0:- cyano-3ethyl-4-methyl-4-thiazoline-A -acetic acid methyl and ethyl ester are obtained, respectively.

In the same manner, but using an equivalent amount of the sodium salt of S-(propylamino)-2-cyano-3-rnercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)-2-cyano-3-mercapt0acrylic acid methyl or ethyl ester, or cyano-3-propyl-4-methyl-4-thiazoline-A -acetic acid methyl and ethyl esters are obtained.

EXAMPLE 4 To a solution of the sodium salt of 3-(methylamino)- Z-cyano-S-mercaptoacrylic acid ethyl ester (prepared as described in Example 1 using 0.05 mole sodium, 0.05 mole methyl isothiocyanate and 0.05 mole ethyl cyanoacetate) in 40 ml. of ethanol is added propargyl bromide (0.05 mole). The mixture is heated on a steam bath for eight hours and left overnight in the cold. The precipitate is collected, washed with water and dried. The precipitate is crystallized from toluene and isopropanol to give a.-

cyano-3-methyl-4-methy1ene-A thiazolidineacetic acid ethyl ester (VI, R =C H and R =CH 2-NMR in CHCl ,=CH at 240 and 260 cps. NMR in CHCl ,=CH at 240 and 260 c.p.s.

In the same manner, but using an equivalent amount of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid methyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)- 2-cyano-3-mercaptoacrylic acid ethyl ester, a-cyano-I'amethyl-4-methylene-A --thiazoidineactic acid methyl ester is obtained.

In the same manner, but using an equivalent amount of the sodium salt of 3-(ethylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(methy1amino)- 2-cyano-3-mercaptoacrylic acid ethyl ester, a-cyano-3- ethyl-4-rnethylene-A thiazolidineacetic acid methyl and ethyl esters are obtained, respectively.

In the same manner, but using an equivalent amount of the sodium salt of 3-(propylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester prepared as described in Example 1, instead of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, a-cyano 3 propyl-4-methylene-A --thiazolidineacetic acid methyl and ethyl esters are obtained, respectively.

EXAMPLE 5 To a solution of the sodium salt of 3-(ethylamino)-2- cyano-3-mercaptoacrylic acid ethyl ester (prepared as described in Example 1 using 0.05 mole sodium, 0.05 mole ethyl isothiocyanate and 0.05 mole ethyl cyanoacetate) in 40 ml. of ethanol is added propargyl bromide (0.05 mole). The mixture is heated on a steam bath for eight hours, cooled and rendered acidic with acetic acid and left overnight in the cold. The resulting precipitate is collected and crystallized from isopropanol and toluene to afford a-cyano-3 -ethyl-4-methyl-4-thiazoline-A -"-acetic acid ethyl ester, (I, R and R =C H M.P. 11lll2 C.

In the same maner, but using an equivalent amount of the sodium salt of 3-(ethylamino)-2-cyano-3-mercaptoacrylic acid methyl ester, prepared as described in Example l, instead of the sodium salt of 3-(ethylamino)-2- cyano-3-mercaptoacrylic acid ethyl ester, u-cyano-3-ethyl- 4-methyl-4-thiazoline-A --acetic acid methyl ester is obtained.

In the same manner, but using an equivalent amount of the sodium salt of 3-(methylamino)-2-cyano-3-mercaptoacrylic acidmethyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(ethylamino)-2-cyano-3-mercaptoacrylic acid ethyl ester, a-cyano-3-methyl-4-methyl-4-thiazoline-A -acetic acid methyl and ethyl esters are obtained, respectively.

In the same manner, but using an equivalent amount of the sodium salt of 3-(propylamino)-2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, prepared as described in Example 1, instead of the sodium salt of 3-(ethylamino)- 2-cyano-3-mercaptoacrylic acid methyl or ethyl ester, 0:- cyano-3-propyl-4-methyl-thiazoline-A --acetic acid methyl and ethyl esters are obtained, respectively.

I claim: v

1. A compound selected from those of the formula Hi Z-oooru wherein R represents a lower alkyl group containing from one to two carbon atoms and R represents a lower alkyl group containing from one to three carbon atoms.

2. A compound as described in claim 1 which is: acyano 3,4 dimethyl-4-thiazoline-A -acetic acid ethyl ester.

3. A compound as described in claim 1 which is: acyano 3,4-dimethyl-4-thiazoline-A '-acetic acid methyl ester.

4. A compound as described in claim 1 which is: (xcyano-3-ethyl-4-methyl-4-thiazoline-A '-acetic acid methyl ester.

5. A compound as described in claim 1 which is: acyano-3-ethyl-4-methyl-4-thiazolineA -acetic acid ethyl ester.

6. A compound as described in claim 1 which is: ucyano 3 propyl-4-methyl-4-thiazoline-A -acetic acid methyl ester.

7. A compound as described in claim 1 which is: oncyano-3-propyl-4-methyl-4-thiazoline-A -acetic acid ethyl ester.

References Cited UNITED STATES PATENTS 3,110,712 11/1963 Hill et al 260-306.7

ALEX MAZEL, Primary Examiner R. D. GALLAGHER, Assistant Examiner US. Cl. X.R.

mg UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent: No. 3, 9 ,997 Q Dated March 3, 1970 Inventor(s) Real Laliberte It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

r- Column 3, Formula V (middle formula, right hand side) H r'- c 2 1 3 J --"N R COOR l HQC C S CH should read:

7 SIGNED Am SEALED Edmd WILLIAM 2. am, at. Arr i Offi Commissioner of Patonts 

